Analgesic benzoxazolinones having at the 6-position a 1-hydroxy-3-morpholinopropyl side chain

ABSTRACT

Compounds of general formula (I): ##STR1## in which: R 1  denotes a hydrogen atom or a lower alkyl optionally substituted with a hydroxyl group, 
     R 2  and R 3  : 
     a- identical or different, denote a hydrogen atom, a lower alkyl, a lower alkenyl, a substituted or unsubstituted aryl, a substituted or unsubstituted (lower alkyl)aryl, 
     b- are such that they form, with the nitrogen which carries them, a saturated or unsaturated, mono- or bicyclic heterocyclic system containing at most 3 hetero atoms per ring, substituted or unsubstituted, with the exception of 1-arylpiperazine systems, 
     X denotes a hydrogen atom, 
     Y denotes a hydrogen atom or a hydroxyl, 
     or alternatively X and Y denote an oxygen atom, provided that 
     R 1  is then other than a methyl group, 
     Z denotes a hydrogen atom or forms a π bond with Y, and 
     T denotes a hydrogen atom or a lower alkyl, their stereoisomers and their quaternary ammonium salts, as well as their addition salts with a pharmaceutically acceptable acid having analgesic or arterial antihypertensive property. 
     Medicinal products.

The present application is a division of our prior-filed copending U.S.application Ser. No. 07/485,057, filed Feb. 26, 1990, now U.S. Pat. No.5,132,305.

The present invention relates to new benzoxazolinone compounds, to theirpreparation and to pharmaceutical compositions containing them.

Many benzoxazolinone derivatives have been described in therapeutics aspossessing a wide variety of pharmacological activities. French Patent73/23,280 describes 6-acylbenzoxazolinones as analgesics French Patent80/20,861 describes, in particular, 6-(2-aminoethyl)benzoxazolinones and6-(aminoacetyl)benzoxazolinones which are usable in the treatment ofarterial hypertension as well as in that of painful syndromes. FrenchPatent 82/19,812 describes 6 -(2-aminoethyl)benzoxazolinones which areusable in therapy in the treatment of sleep disorders and character andbehavioral disorders.

The Applicant has now discovered benzoxazolinone derivatives endowedwith an analgesic activity which is devoid of anti-inflammatoryactivity, of a markedly more advantageous level than that of thederivatives described in French Patents 73/23,280 and 80/20,861. Thecompounds of the present invention are, in effect, endowed with ahigh-level pure analgesic activity. In point of fact, most non-morphinicanalgesic substances known to date also possess anti-inflammatoryactivity (for example salicyl derivatives, pyrazole derivatives, etc.),and they consequently intervene in the processes occurring ininflammation. These processes involve a very large number of chemicalmediators (prostaglandins, thromboxane A2, etc.); multifarious sideeffects accordingly ensue, the best known of which are attack of thegastric mucosa with the possibility of ulcers. Apart from thedisturbances they cause, these concomitant effects prohibit the use ofthese products in many subjects who are especially sensitive to them.Being devoid of all anti-inflammatory activity, the compounds of thepresent invention do not interact with the mediators of inflammation andare hence devoid of the side effects mentioned above. This feature,combined, in the case of a number of the compounds, with a completeabsence of toxicity and a high level of activity, renders some compoundsof the present invention usable as analgesics much more safely andwithout the restrictions in use customarily known for the great majorityof these products. Some compounds of the invention exhibit, in addition,advantageous activity on arterial blood pressure and on the centralnervous system.

More specifically, the invention relates to the compounds of generalformula (I): ##STR2## in which: R₁ denotes a hydrogen atom or a loweralkyl group optionally substituted with a hydroxyl group,

R₂ and R₃, which may be identical or different, denote

a hydrogen atom,

a linear or branched lower alkyl group,

a linear or branched lower alkenyl group,

an aryl or (lower alkyl)aryl group in which the aryl portion isoptionally substituted with one or more halogen atoms, or lower alkylgroups optionally substituted with one or more halogen atoms, or loweralkoxy groups, or alternatively R₂ and R₃ form, with the nitrogen atomto which they are attached, a saturated or unsaturated, mono- orbicyclic heterocyclic system containing one, two or three hetero atomsper ring, chosen from nitrogen, oxygen or sulfur, unsubstituted orsubstituted with a halogen or a lower alkyl, lower alkoxy or aryl groupoptionally substituted with one or more halogen atoms, provided that R₂and R₃ do not form a 1-arylpiperazine system with the nitrogen atom towhich they are attached,

X denotes a hydrogen atom,

denotes a hydrogen atom or a hydroxyl group, or alternatively X and Ytogether denote an oxygen atom provided that, in this case, R is otherthan a methyl group,

Z denotes a hydrogen atom or alternatively Z forms a π bond with Y, and

T denotes a hydrogen atom or a lower alkyl group,

the term lower indicating that the groups so described have from 1 to 6carbon atoms,

their enantiomers, diastereoisomers and epimers and their quaternaryammonium salts as well as their addition salts with a pharmaceuticallyacceptable acid.

Among acids which may be used for salifying compounds of general formula(I), hydrochloric, sulfuric, phosphoric, tartaric, malic, maleic,fumaric, oxalic, methanesulfonic, ethanesulfonic, camphoric and citricacids, and the like, may be mentioned without implied limitation.

The invention also encompasses two processes for the production of thecompounds of formula (I).

Depending on the compounds of the invention which it is desired toobtain, it may, in effect, be advantageous to use either one process orthe other.

The first process for preparing the compounds of formula (I), which isespecially advantageous for the production of the compounds of formula(I) in which X, Y and Z each denote a hydrogen atom, can nevertheless beapplied for the derivatives in which X, Y and Z have other meanings, andemploys as starting material a derivative of formula (II): ##STR3## inwhich R'₁ denotes a hydrogen atom or a lower alkyl group, the compoundbeing obtained, for example, by the reaction of ortho-aminophenol withurea followed, when R'₁ is other than H, by an alkylation on thenitrogen, which compounds is subjected to the action of an acid chlorideof formula (III): ##STR4## in which T has the same meaning as in theformula (I), A denoting a halogen atom,

or alternatively of the corresponding acid anhydride, in the presence ofaluminum chloride in dimethylformamide according to the conditions ofTHYES et al. (J. Med. Chem. 1983, 26, 6, 800-807), to obtain a compoundof formula (IV): ##STR5## in which R'₁, T and A have the same meaning asabove, which, if so desired, is subjected to reduction with atrialkylsilane in an acid medium according to the conditions describedby WEST et al. (J. Org. Chem. 1973, 38, (15), 2675-2681), to lead to acompound of formula (V): ##STR6## in which R'₁, T and A have the samemeaning as above, the compound of formula (IV) or the compound offormula (V), depending on the formula of the compound of formula (I)which it is desired to obtain, then being subjected to the action of anamine of formula (VI): ##STR7## in which R₂ and R₃ have the same meaningas in the formula (I), in a solvent preferably chosen from acetone,acetonitrile, ethyl acetate, lower aliphatic alcohol, dioxane, benzeneand toluene, at a temperature between room temperature and the boilingpoint of the chosen solvent, in the presence of an excess of the chosenamine or of a trapping agent for the hydracid formed, such astriethylamine,

to lead to a compound of formula (I/A): ##STR8## in which, depending onwhether the starting material used is a compound of the formula (IV) or(V),

X' and Y' together denote an oxygen atom, or alternatively X' and Y'each simultaneously denote a hydrogen atom,

R'₁, R₂, R₃ and T having the same meaning as above,

which, if so desired, is salified with a pharmaceutically acceptableacid or which can, when X' and Y' together denote an oxygen atom, if sodesired, be subjected

either to a hydrogenating agent chosen from an alkali metal mixedhydride such as, for example, sodium borohydride, or an alkali metalmixed cyanohydride such as sodium cyanoborohydride, preferably in alower aliphatic alcohol medium, to lead to a compound, of formula(I/B)--predominantly in the threo configuration when T does not denote ahydrogen atom: ##STR9## a special case of the compounds of formula (I)in which: R'₁, R₂, R₃ T have the same meaning as above,

X denotes a hydrogen atom,

Y a hydroxyl group and Z a hydrogen atom,

the isomers of which are separated if so desired, and/or which issalified with a pharmaceutically acceptable acid,

or alternatively to catalytic hydrogenation, with heating and underpressure in a solvent chosen from lower aliphatic alcohol or dioxane, tolead to a compound of formula (I/B)--essentially in the erythroconfiguration when T does not denote a hydrogen atom the isomers ofwhich are separated if so desired, and which is salified, whereappropriate, with a pharmaceutically acceptable acid,

which compound of formula (I/B), irrespective of the process accordingto which it has been obtained, can, if so desired, be treated with adehydrating agent, preferably chosen from hydracids, to lead to acompound formula (I/C): ##STR10## predominantly in the form of the transisomer, a special case of derivatives of formula (I) in which:

R'₁, R₂, R₃ and T have the same meaning as above,

X denotes a hydrogen atom,

Z forms a π bond with Y,

the cis/trans isomers of which are separated, if so desired, by afamiliar technique such as chromatography on a silica column orcrystallization, and which, if so desired, may be salified with apharmaceutically acceptable acid,

which compound of formula (I/A), (I/B) or (I/C), when R'₁ denotes ahydrogen atom, may be treated in the presence of a strong base with acompound of formula X--(CH₂)_(n) --OH,

in which X denotes a halogen atom and n is between 1 and 6, to lead to acompound of formula (I) for which R₁ denotes a lower alkyl groupsubstituted with a hydroxyl group,

which compound of formula (I) may be treated, if so desired, with aconventional alkylating agent such as methyl sulfate to lead to aquaternary ammonium salt.

The second process for the production of the compounds of the presentinvention is inapplicable for the compounds for which R₁ denotes ahydrogen atom or an alkyl group substituted with a hydroxyl group.

In this second process, a compound of formula (II), obtained as statedabove: ##STR11## in which R₁₁ denotes a lower alkyl group, is acylatedwith an acid of formula (VII): ##STR12## in which T has the same meaningas in the formula (I), or the corresponding chloride or anhydride of theacid, according to the conditions described in French Patent 73/23,280,

to obtain a compound of formula (VIII): ##STR13## in which R₁₁ denotes alower alkyl group and T has the same meaning as in the formula (I),

which is then treated

either according to the conditions of the Mannich reaction, which arewell known to those versed in the art, in the presence oftrioxymethylene and of the amine of formula (VI): ##STR14## in which R₂and R₃ have the same meaning as in the formula (I), to obtain a compoundof formula (I/A1): ##STR15## a special case of the compounds of formulae(I/A) and (I) in which formula:

R₁₁ denotes a lower alkyl group, and R₂, R₃ and T have the same meaningas in the formula (I),

X and Y here simultaneously denote an oxygen atom and Z a hydrogen atom,

or alternatively with bis(dimethylamino)methane in the presence ofacetic anhydride to obtain a product of general formula (IX): ##STR16##in which: T has the same meaning as in the formula (I) and R₁₁ denotes alower alkyl group,

which is treated with an amine of formula (VI), in a polar solvent at atemperature between room temperature and the boiling point of thereaction medium, to lead to a compound of formula (I/AI) defined above,which, when T does not denote a hydrogen atom, can, if so desired, beseparated into its isomers, which are salified, if so desired, with apharmaceutically acceptable acid, and which can if so desired, besubjected:

either, preferably in a lower aliphatic alcohol medium, to ahydrogenating agent, preferably an alkali metal mixed hydride or analkali metal mixed cyanohydride such as, for example, sodium borohydrideor sodium cyanoborohydride,

to lead to a compound . of formula (I/B), predominantly in the threoconfiguration (when T does not denote a hydrogen atom): ##STR17## aspecial case of the compounds of formula (I) in which: R₁₁, R₂, R₃ and Thave the same meaning as above,

X denotes a hydrogen atom,

Y a hydroxyl group and Z a hydrogen atom,

the isomers of which are separated if so desired, and which may besalified with a pharmaceutically acceptable acid,

or alternatively to catalytic hydrogenation, in a solvent chosen fromlower aliphatic alcohol or dioxane, to lead to a compound of formula(I/B), essentially in the erythro configuration--when T does not denotea hydrogen atom--the isomers of which are separated if so desired, andwhich is salified, where appropriate, with a pharmaceutically acceptableacid,

which compound of formula (I/B) is, where appropriate, subjected to adehydrating agent preferably chosen from hydracids, to lead to acompound of formula (I/C), predominantly in the form of trans isomers:##STR18## a special case of compounds of formula (I) in which: R₁₁, R₂,R₃ and T have the same meaning as in the compounds of formula (I),

X denotes a hydrogen atom,

Z forms a π bond with Y,

the cis/trans isomers of which are separated, if so desired, by afamiliar technique such as chromatography on a silica column orcrystallization,

and which is salified, if so desired, with a pharmaceutically acceptableacid,

which, if so desired, is subjected to a catalytic hydrogenationreaction, preferably at room temperature and atmospheric pressure and inthe presence of Raney nickel in a lower aliphatic alcohol or dioxanemedium, to obtain a compound of formula (I/D): ##STR19## in which: R₁₁,R₂, R₃ and T have the same meaning as above,

X, Y and Z each simultaneously denotes a hydrogen atom,

the isomers of which are separated, where appropriate, when T does notdenote a hydrogen atom,

and which is optionally salified with a pharmaceutically acceptable acidor which is converted to a quaternary ammonium salt by the action of analkylating agent as stated above.

The compounds of formula (I/D) may also be obtained from the derivativesof formula (IX): ##STR20## in which: R₁₁ and T have the same meaning asabove, which are treated with a hydracid to obtain a derivative offormula (IV): ##STR21## in which R₁₁ and T have the same meaning asabove and A the same meaning as in the formula (III),

the isomers of which are separated, if so desired, when T does notdenote a hydrogen atom,

which is subjected to reduction with a trialkylsilane in an acid mediumaccording to the conditions described by WEST et al. (J. Org. Chem 1973,38, (15), 2675-2681), to lead to a compound of formula (V): ##STR22## inwhich R₁₁ and T have the same meaning as above and A the same meaning asin the formula (III),

which is subjected to the action of an amine of formula (VI): ##STR23##in which R₂ and R₃ have the same meaning as in the formula (I), in asolvent preferably chosen from acetone, acetonitrile, ethyl acetate,lower aliphatic alcohol, dioxane, benzene and toluene, at a temperaturebetween room temperature and the boiling point of the chosen solvent, inthe presence of an excess of the chosen amine or of a trapping agent forthe hydracid formed, such as triethylamine,

to lead to a compound of formula (I/D) designated above, which issalified, if so desired, with a pharmaceutically acceptable acid orwhich is converted to a quaternary ammonium salt with an alkylatingagent.

The compounds of formula (I) possess advantageous pharmacologicalproperties.

In particular, these compounds have evinced an advantageous analgesicactivity as well as, in the case of some of these compounds, an activityon the central nervous system and on arterial blood pressure.

A pharmacological study of the compounds of the invention showed, ineffect, that they were of low toxicity, endowed with a pure analgesicactivity and hence devoid of drawbacks inherent in most non-morphiniccompounds exhibiting this activity (ulcerogenic action on the mucosae,etc.). This spectrum of activity hence renders the compounds of thepresent invention advantageous in a number of indications such asrheumatic pain, lumbosciatic neuralgia, cervicobrachial neuralgia, painassociated with trauma such as sprains, fractures, dislocations,post-traumatic pain, postoperative pain, dental pain, neurological painsuch as facial neuralgia, visceral pain such as nephritic colic, painassociated with dysmenorrhea and proctological surgery, pain of the ENTregion, pancreatitis, various pains, headache, cancer pain, etc.

The subject of the present invention is also pharmaceutical compositionscontaining the products of formula (I), alone or in combination with oneor more pharmaceutically acceptable, non-toxic, inert vehicles orexcipients.

Among pharmaceutical compositions according to the invention, there maybe mentioned, more especially, those which are suitable for oral,parenteral and nasal administration, simple or sugar-coated tablets,sublingual tablets, sachets, packets, gelatin capsules, sublingualpreparations, pills, suppositories, creams, ointments, skin gels, andthe like.

The appropriate dosage varies according to the patient's age and weight,the administration route, the nature of the therapeutic indication andany associated treatments, and ranges between 1 centigram and 4 gramsper 24 hours.

The examples which follow illustrate the invention and in no way limitthe latter.

The infrared spectra were run using a potassium bromide disk containingapproximately 1% of the test product.

EXAMPLE 1: 3-METHYL-6-[3-(1-PIPERIDYL)PROPYL]BENZOXAZOLINONE(HYDROCHLORIDE) Stage A: 3-methyl-6-(3-chloropropionyl)benzoxazolinone

6.02 ml (0.078 mole) of dimethylformamide are introduced dropwise andwith stirring into a ground-necked flask containing 37.4 g (0.28 mole)of anhydrous aluminum chloride.

The flask is equipped with a reflux condenser and taken to an oil bathat a temperature in the region of 40°-45° C. 0.04 mole of3-methylbenzoxazolinone and 0.44 mole of 3-chloropropionic acid chlorideare introduced. The mixture is heated to a temperature in the region of75° C. for 2 hours 30 minutes. After cooling, the reaction mixture ispoured into 300 g of ice, acidified with concentrated hydrochloric acidand stirred for hour 30 minutes. The precipitate obtained is drained,washed with water and dried. The product is recrystallized in ethanol.

Yield: 88%.

Melting point: 187° C.

Infrared: ν CO (carbamate): 1765 cm⁻¹ ; ν CO (ketone): 1660 cm⁻¹ ;

Stage B: 3-methyl-6-(3-chloropropyl)benzoxazolinone

0.02 mole of 3-methyl-6-(3-chloropropionyl)benzoxazolinone, obtained inthe preceding stage, is dissolved in 22.8 g (0.2 mole) oftrifluoroacetic acid in a ground-necked flask 0.044 mole oftriethylsilane is added dropwise and while cooling. A calcium chlorideguard tube is fitted and stirring is continued for 72 hours. Thereaction medium is then poured into ice-cold water and the precipitateobtained is drained, dried and recrystallized in hexane.

Yield: 80%.

Melting point 70° C.

Infrared: ν CO (carbamate): 1775 cm⁻¹ ;

Stage C: 3-methyl-6-[3-(1-piperidyl)propyl]benzoxazolinone(Hydrochloride)

0.02 mole of 3-methyl-6-(3-chloropropyl)benzoxazolinone, obtained instage B, is dissolved in acetonitrile in a 250-cm³ ground-necked flaskequipped with a condenser 0.04 mole of piperidine is added with magneticstirring and the mixture is brought to reflux for 48 hours. Aftercooling of the solution, the insoluble matter formed is filtered off andthe filtrate is then evaporated on a water bath under vacuum. Theresidue is taken up with 500 cm³ of water and the mixture is alkalinizedwith 10% strength aqueous sodium hydroxide solution. The precipitate isdrained and washed with water until the aqueous phase is neutral, andthe compound is then dissolved in hexane and a stream of gaseoushydrochloric acid is bubbled through. The product is drained, dried andrecrystallized in ethanol.

Yield: 69%.

Melting point: 238° C.

Infrared: ν CO: 1770 cm⁻¹.

EXAMPLE 2: 3-METHYL-6-[3-(4-METHYL-1-PIPERAZINYL)PROPYL]BENZOXAZOLINONE(DIHYDROCHLORIDE)

0.02 mole of 3-methyl-6-(3-chloropropyl)benzoxazolinone, obtained instage B of Example 1, is dissolved in dioxane in a 250-cm³ ground-neckedflask equipped with a condenser 0.04 mole of N-methylpiperazine is addedwith stirring and the mixture is brought to reflux for 48 hours Aftercooling of the solution, the insoluble matter is filtered off and thefiltrate is then evaporated on a water bath under vacuum. The residue istaken up with 500 cm³ of water and the mixture is alkalinized with 10%strength aqueous sodium bicarbonate solution and extracted withchloroform. The organic phase is dried over calcium chloride, filteredand evaporated to dryness. An oily product is obtained, which is takenup with acetone. After gaseous hydrochloric acid has been bubbledthrough this solution, the product is drained, dried and recrystallizedin a methanol/acetone mixture.

Yield: 53%.

Melting point: >270° C.

Infrared: ν CO: 1770 cm⁻¹.

EXAMPLE 3: 3-METHYL-6-[3-(1-PYRROLIDINYL)PROPYL]BENZOXAZOLINONE(HYDROCHLORIDE)

0.02 mole of 3-methyl-6-(3-chloropropyl)benzoxazolinone, obtained instage B of Example 1, is dissolved in acetonitrile in a 250-cm³ground-necked flask equipped with a condenser. 0.04 mole of pyrrolidine,0.02 mole of potassium iodide and 0.02 mole of sodium carbonate areadded with stirring and the mixture is brought to reflux for 4 days.After cooling of the solution, the insoluble matter is filtered off andthe filtrate is then evaporated on a water bath under vacuum. Theresidue is taken up in ether, the remaining insoluble matter is filteredoff and a stream of gaseous hydrochloric acid is bubbled through thissolution. The product is drained, dried and recrystallized in acetone.

Yield: 69%.

Melting point: 174° C.

Infrared ν CO: 1770 cm⁻¹.

EXAMPLE 4: 3-METHYL-6-(1-HYDROXY-3-MORPHOLINOPROPYL)BENZOXAZOLINONEStage A: 3-methyl-6-(3-morpholinopropionyl)benzoxazolinone

0.03 mole of 6-acetyl-3-methylbenzoxazolinone, obtained as described inFrench Patent 73/23,280, and 0.045 mole of morpholine hydrochloride aredissolved in 150 cm³ of absolute ethanol in a 250-cm³ ground-neckedflask equipped with a condenser 0.045 mole of trioxymethylene is addedand the mixture is acidified with hydrochloric acid. The mixture isheated to reflux for 64 hours. The precipitate formed is drained, washedwith acetone and suspended in water and the mixture is alkalinized withsodium hydroxide. The mixture is extracted several times withchloroform, the organic phases are dried over sodium chloride, filteredand evaporated on a water bath under vacuum and the product isrecrystallized in ethanol.

Yield: 55%.

Melting point: 134° C.

Infrared ν CO (carbamate): 1770 cm⁻¹ ; νCO (ketone): 1660 cm⁻¹.

STAGE B: 3-methyl-6-(1-hydroxy-3-morpholinopropyl)benzoxazolinone

0.01 mole of 3-methyl-6-(3-morpholinopropionyl)benzoxazolinone, preparedin stage A, is dissolved in 200 cm³ of methanol in a 250-cm³ flaskequipped with a magnetic stirrer 0.02 mole of sodium borohydride isadded very slowly and with stirring. Stirring is continued for 4 hoursat room temperature. The reaction medium is evaporated on a water bathunder vacuum. The residue is taken up with water and the mixture isextracted several times with chloroform. The extracts are filtered andevaporated to dryness on a water bath under vacuum and the product isrecrystallized in cyclohexane.

Yield: 68%.

Melting point: 115° C.

Infrared: ν CO: 1755 cm⁻¹.

EXAMPLE 5: 3-METHYL-6-(3-MORPHOLINO-1-PROPENYL)BENZOXAZOLINONE

0.015 mole of 3-methyl-6-(1-hydroxy-3-morpholinopropyl)benzoxazolinone,obtained in Example 4, is dissolved in 50 cm³ of 47% strengthhydrobromic acid in a 250-cm³ flask, and the solution is stirred at roomtemperature for 2 hours. The precipitate is drained, washed with acetoneand suspended in water and the mixture is alkalinized with sodiumhydroxide. The mixture is extracted several times with chloroform, theorganic phases are combined and dried over calcium chloride, filteredand evaporated to dryness under vacuum and the product is recrystallizedin propanol.

Yield: 64%.

Melting point: 132° C.

Infrared: ν CO: 1765 cm¹.

EXAMPLE 6: 3-METHYL-6-(3-MORPHOLINOPROPYL)BENZOXAZOLINONE

0.01 mole of 3-methyl-6-[(3-morpholino)-1-propenyl]benzoxazolinone,obtained in Example 5, is dissolved in methanol in a 500-cm³ conicalflask equipped with a three-way tap and a magnetic stirrer, and 0.5 g ofRaney nickel is then added. The mixture is stirred under a hydrogenatmosphere at room temperature and atmospheric pressure. After thetheoretical amount of hydrogen has been absorbed, the reaction medium isfiltered and the filtrate is evaporated to dryness on a water bath undervacuum. The residue is taken up with water, the mixture is acidifiedwith hydrochloric acid and the precipitate is drained and recrystallizedin ethyl acetate.

Yield: 86%.

Melting point: 226° C.

Infrared: ν CO: 1770 cm⁻¹.

EXAMPLE 7: 3-METHYL-6-(3-MORPHOLINOPROPYL)BENZOXAZOLINONE

Using the procedure described in Example 1, but replacing piperidine(stage C) by morpholine, the expected product is obtained.

EXAMPLE 8: 3-METHYL-6-(3-DIETHYLAMINOPROPYL)BENZOXAZOLINONE

Using the procedure described in Example 1, but replacing piperidine(stage C) by N,N-diethylamine, the expected product is obtained.

Melting point: 131°-132° C.

EXAMPLE 9: 6-(3-MORPHOLINOPROPYL)BENZOXAZOLINONE (HYDROCHLORIDE) StageA: 6-(3-chloropropionyl)benzoxazolinone

56.1 g (0.42 mole) of aluminum chloride are weighed into a ground-neckedflask, 10 cm³ of dimethylformamide are then added using a droppingfunnel and the mixture is left stirring until it becomes homogeneous.8.1 g (0.06 mole) of benzoxazolinone are then added and the mixture isleft stirring for 10 minutes before adding (0.072 mole) of3-chloropropionic acid chloride. This mixture is maintained in an oilbath at 80°-85° C. for approximately 2 hours 30 minutes. After cooling,the reaction mixture is poured into ice-cold water. The precipitate isdrained and washed with water to neutrality. The product isrecrystallized in ethanol.

Yield: 70%.

Melting point: 166° C.

Infrared: ν CO (carbamate): 1760 cm⁻¹ ; ν CO (ketone): 1655 cm⁻¹.

Stage B: 6-(3-chloropropyl)benzoxazolinone

9 g (0.04 mole) of 6-(3-chloropropionyl)benzoxazolinone, obtained instage A, and 31 cm³ of trifluoroacetic acid are introduced into aground-necked flask 13.5 cm³ (0.09 mole) of triethylsilane are addeddropwise using a dropping funnel and with stirring. The dropping funnelis replaced by a calcium chloride guard tube and the mixture is leftstirring at room temperature for 48 hours. The reaction mixture is thenpoured into ice-cold water and the mixture is left stirring for 2 hours.The precipitate is drained and washed with water to neutrality. Theproduct is recrystallized in toluene.

Yield: 70%.

Melting point: 127° C.

Infrared: ν CO: 1770 cm⁻¹.

Stage C: 6-(3-morpholinopropyl)benzoxazolinone (Hydrochloride)

4.2 g (0.02 mole) of 6-(3-chloropropyl)benzoxazolinone are dissolved in100 cm³ of acetonitrile in a round-bottomed flask. 2.0 g (0.02 mole) ofmorpholine and 2.4 g (0.02 mole) of triethylamine are added and themixture is left stirring under reflux for 5 days. After cooling, thereaction mixture is evaporated to dryness, the residue is taken upseveral times with anhydrous acetone and the triethylamine hydrochlorideformed is filtered off. The acetone is evaporated off, the residue istaken up with an acetone/hexane mixture and a stream of gaseoushydrochloric acid is bubbled through this solution. The precipitate isdrained and dried and then recrystallized in acetone.

Yield: 43%.

Melting point: 120° C.

Infrared: ν CO: 1750 cm⁻¹.

EXAMPLE 10: 6-[3 -(1-PIPERIDYL)PROPYL]BENZOXAZOLINONE

Using the procedure described in Example 9, but replacing morpholine(stage C) by piperidine, the expected product is obtained.

EXAMPLE 11: 6-[3-(4-METHYL-1-PIPERAZINYL)PROPYL]BENZOXAZOLINONE

Using the procedure described in Example 9, but replacing morpholine(stage C) by 4-methylpiperazine, the expected product is obtained.

EXAMPLE 12: 6-[3-(1-PYRROLIDINYL)PROPYL]BENZOXAZOLINONE

Using the procedure described in Example 9, but replacing morpholine(stage C) by pyrrolidine, the expected product is obtained.

EXAMPLE 13: 6-(3-DIETHYLAMINOPROPYL)BENZOXAZOLINONE

Using the procedure described in Example 9, but replacing morpholine(stage C) by diethylamine, the expected product is obtained.

EXAMPLE 14: 3-METHYL-6-[3-(3-THIAZOLIDINYL)PROPYL]BENZOXAZOLINONE

Using the procedure described in Example 1, but replacing piperidine(stage C) by thiazolidine, the expected product is obtained.

EXAMPLE 15 6-[3-(3-THIAZOLIDINYL)PROPYL]BENZOXAZOLINONE

Using the procedure described in Example 9, but replacing morpholine(stage C) by thiazolidine, the expected product is obtained.

EXAMPLE 16: 3-METHYL-6-(3-DIMETHYLAMINOPROPYL)BENZOXAZOLINONE

Using the procedure described in Example 1, but replacing piperidine(stage C) by dimethylamine, the expected product is obtained.

EXAMPLE 17 6-(3-DIMETHYLAMINOPROPYL)BENZOXAZOLINONE

Using the procedure described in Example 9, but replacing morpholine(stage C) by dimethyl-amine, the expected product is obtained.

EXAMPLE 18: 3-METHYL-6-[3-(1-INDOLINYL)PROPYL]BENZOXAZOLINONE

Using the procedure described in Example 1, but replacing piperidine(stage C) by indoline, the expected product is obtained.

EXAMPLE 19: 6-[3-(1-INDOLINYL)PROPYL]BENZOXAZOLINONE

Using the procedure described in Example 9, but replacing morpholine(stage C) by indoline, the expected product is obtained.

EXAMPLE 20: 3-METHYL-6-[1-HYDROXY-3-(1-PIPERIDYL)PROPYL]BENZOXAZOLINONE

Using the procedure described in Example 4, but replacing morpholinehydrochloride (stage A) by piperidine hydrochloride, the expectedproduct is obtained.

EXAMPLE 21: 3-METHYL-6-(3-PIPERIDYL-1-PROPENYL)BENZOXAZOLINONE

Using the procedure described in Example 5, but replacing3-methyl-6-(1-hydroxy-3-morpholinopropyl)benzbenzoxazolinone by3-methyl-6-(1-hydroxy-3-piperidylpropyl)benzoxazolinone (Example 20),the expected product is obtained.

EXAMPLE 22: 3-METHYL-6-[3-(1-PIPERIDYL)PROPYL]BENZOXAZOLINONE

Using the procedure described in Example 6, but replacing3-methyl-6-(3-morpholino-1-propenyl)benzoxazolinone by3-methyl-6-(3-piperidyl-1-propenyl)benzoxazolinone (Example 21), theexpected product is obtained.

EXAMPLE 23:3-METHYL-6-[1-HYDROXY-3-(4-METHYL-1-PIPERAZINYL)PROPYL]BENZOXAZOLINONE

Using the procedure described in Example 4, but replacing morpholinehydrochloride (stage A) by 1-methylpiperazine dihydrochloride, theexpected product is obtained.

EXAMPLE 24:3-METHYL-6-[3-(4-METHYL-1-PIPERAZINYL)-1-PROPENYL]BENZOXAZOLINONE

Using the procedure described in Example 5, but replacing3-methyl-6-(1-hydroxy-3-morpholinopropyl)benzoxazolinone by3-methyl-6-[1-hydroxy-3-(4-methyl-1piperazinyl)propyl]benzoxazolinone(Example 23), the expected product is obtained.

EXAMPLE 25: 3-METHYL-6-[3-(4-METHYL-1-PIPERAZINYL)PROPYL]BENZOXAZOLINONE

Using the procedure described in Example 6, but replacing3-methyl-6-(3-morpholino-1-propenyl)benzoxazolinone by3-methyl-6-[3-(4-methyl-1-piperazinyl)-1propenyl]benzoxazolinone(Example 24), the expected product is obtained.

EXAMPLE 26: 3-METHYL-6-(1-HYDROXY-3-DIMETHYLAMINOPROPYL)BENZOXAZOLINONE

Using the procedure described in Example 4, but replacing morpholinehydrochloride (stage A) by dimethylamine hydrochloride, the expectedproduct is obtained.

EXAMPLE 27: 3-METHYL-6-(3-DIMETHYLAMINO-1-PROPENYL)BENZOXAZOLINONE

Using the procedure described in Example 5, but replacing3-methyl-6-(1-hydroxy-3-morpholinopropyl)benzoxazolinone by3-methyl-6-(1-hydroxy-3-dimethylaminopropyl)benzoxazolinone (Example26), the expected product is obtained.

EXAMPLE 28: 3-METHYL-6-(3-DIMETHYLAMINOPROPYL)BENZOXAZOLINONE

Using the procedure described in Example 6, but replacing3-methyl-6-(3-morpholino-1-propenyl)benzoxazolinone by3-methyl-6-(3-dimethylamino-1-propenyl)benzoxazolinone (Example 27), theexpected product is obtained.

EXAMPLE 29:3-METHYL-6-[1-HYDROXY-3-(1-PYRROLIDINYL)PROPYL]BENZOXAZOLINONE

Using the procedure described in Example 4, but replacing morpholinehydrochloride (stage A) by pyrrolidine dihydrochloride, the expectedproduct is obtained.

EXAMPLE 30: 3-METHYL-6-[3-(1-PYRROLIDINYL)1-PROPENYL]BENZOXAZOLINONE

Using the procedure described in Example 5, but replacing3-methyl-6-(1-hydroxy-3-morpholinopropyl)benzoxazolinone by3-methyl-6-[1-hydroxy-3-(1-pyrrolidinyl)propyl]benzoxazolinone (Example29), the expected product is obtained.

EXAMPLE 31: 3-METHYL-6-[3-(1-PYRROLIDINYL)PROPYL]BENZOXAZOLINONE

Using the procedure described in Example 6, but replacing3-methyl-6-(3-morpholino-1-propenyl)benzoxazolinone by3-methyl-6-[3-(1-pyrrolidinyl)-1-propenyl]benzoxazolinone (Example 30),the expected product is obtained.

EXAMPLE 32:3-METHYL-6-[1-HYDROXY-3-(3-THIAZOLIDINYL)PROPYL]BENZOXAZOLINONE

Using the procedure described in Example 4, but replacing morpholinehydrochloride (stage A) by thiazolidine hydrochloride, the expectedproduct is obtained.

EXAMPLE 33: 3-METHYL-6-[3-(3-THIAZOLIDINYL)-1-PROPENYL]BENZOXAZOLINONE

Using the procedure described in Example 5, but replacing3-methyl-6-(1-hydroxy-3-morpholinopropyl)benzoxazolinone by3-methyl-6-[1-hydroxy-3-(3-thiazolidinyl)propyl]benzoxazolinone (Example32), the expected product is obtained.

EXAMPLE 34: 3-METHYL-6-[3-(3-THIAZOLIDINYL)-1-PROPYL]BENZOXAZOLINONE

Using the procedure described in Example 6, but replacing3-methyl-6-(3-morpholino-1-propenyl)benzoxazolinone by3-methyl-6-[3-(3-thiazolidinyl)-1-propenyl]benzoxazolinone (Example 33),the expected product is obtained.

EXAMPLE 35: 6-(3-MORPHOLINOPROPYL)-3-(2-HYDROXYETHYL)BENZOXAZOLINONE(HYDROCHLORIDE)

0.01 mole of 6-(3-morpholinopropyl)benzoxazolinone hydrochloride,obtained in Example 9, is added to sodium ethylate. The reactants areleft in contact for one hour, the mixture is evaporated to dryness, theresidue is taken up with 20 cm³ of DMF and 1.2 equivalents of2-bromoethanol are added in the cold state with stirring. The mixture isstirred overnight at room temperature. The DMF is evaporated off todryness, the residue is taken up with water and the aqueous phase isextracted with chloroform. The extracts are dried over CaCl₂, filteredand evaporated to dryness.

The residue is taken up with an acetone/ether mixture, the resultingmixture is filtered and a stream of gaseous hydrochloric acid is bubbledthrough; the product precipitates. It is recrystallized in propanol.

Yield: 50%.

Melting point: 209°-210° C.

EXAMPLE 36: 6-[3-(N-METHYLMORPHOLINO)PROPYL]-3-METHYLBENZOXAZOLINONEMETHANESULFONATE

0.03 mole of 3-methyl-6-(3-chloropropyl)benzoxazolinone is dissolved in100 cm³ of acetonitrile 5.2 cm³ of morpholine are added and the mixtureis left stirring under reflux for 48 hours. The mixture is cooled anddrained, the filtrate is evaporated, the residue is taken up with waterand the mixture is alkalinized with 19% strength sodium hydroxide. Theaqueous phase is extracted with chloroform and the extracts are driedover calcium chloride, filtered and evaporated to dryness.

The residue is taken up with anhydrous chloroform and 0.03 mole ofmethyl sulfate is added. The mixture is left stirring under reflux forone hour. The product precipitates; it is drained and recrystallized inethanol.

Yield: 65%.

Melting point: 142° C.

Pharmacological Study of the Compounds of the Invention EXAMPLE 37:STUDY OF THE ACUTE TOXICITY

The acute toxicity was assessed after the oral administration of a doseof 1000 mg.kg⁻¹ to batches of 8 mice (26±2 grams). The animals wereobserved at regular intervals during the first day, and daily during the2 weeks following the treatment.

It is apparent that the compounds of the invention are completelynon-toxic. No deaths are observed after administration of a dose of 1000mg.kg⁻¹. No disorders are noted after administration of this dose.

EXAMPLE 38: STUDY OF THE ANALGESIC ACTIVITY

The activity against pain was investigated in mice (23-25 g) accordingto a protocol derived from the technique described by SIEGMUND (SIEGMUNDE.A., R.A. CADMUS & GOLU, J. Pharm. Exp. Ther. 119, 1874, 1954). Themice, randomized in batches of 12 animals, received the treatment orally(excipient for the controls) 1 hour before the intraperitoneal injectionof a 0.02% strength aqueous-alcoholic solution of phenyl-p-benzoquinone(Sigma). The writhing movements are counted between the 5th and 10thminute after injection.

The percentage activity obtained was evaluated for each dose (% decreasein the number of writhing movements in the treated animals relative tothe controls). An ED₅₀, the dose producing a 50% activity, wasdetermined for each product.

It was apparent that some compounds of the invention possess a veryadvantageous analgesic activity. Thus, the ED₅₀ of the compound ofExample 6 is in the region of 5 mg.kg⁻¹.

By way of comparison, the administration of a dose of 100 mg.kg⁻¹ of thecompounds of French Patent 73/23,280 produced a percentage analgesiceffect--in a comparable test--of the order of 25 to 60%, and thecompound of French Patent 80/20,861, the analgesic activity of which isthe most advantageous, had an ED₅₀ of 9 mg.kg⁻¹ in this same Siegmundtest, that is to say almost twice as large as that of the mostadvantageous product of the present invention.

EXAMPLE 39: STUDY OF THE ANTI-INFLAMMATORY ACTIVITY

The anti-inflammatory potential of the compounds was investigated on amodel of acute inflammation induced by the subcutaneous injection of asolution of carrageenan into the rat hind foot, according to a techniquebased on the method of WINTER, C.A., E.A. RISLEY and G.N. NUSS (Proc.Soc. Exp. Med. 111, 554, 1962). The rats (100-120 g), randomized inbatches of 8, were treated (including the controls, which receiveexcipient) 1 hour before the local injection of a 0.5% strengthsuspension of carrageenan (Sigma type IV; 0.1 ml per rat). The edema isdetermined 3 hours after injection, by plethysmometric measurement (UGOBASILE water plethysmometer) of the volume of each of the hind feet(edema=volume of the inflamed foot less the volume of the non-inflamedfoot).

It is apparent that the products of the invention have no activity inthis test. In comparison, the products of French Patent 73/23,280possess an anti-inflammatory activity.

EXAMPLE 40: RESERPINE ANTAGONISM

The reserpine antagonism was assessed after the administration ofreserpine (2.5 mg.kg⁻¹) to a batch of 6 mice. Four hours later, the testcompound is administered intraperitoneally. A control batch receives noproduct.

Two parameters are observed rectal temperature and ptosis. In thecontrols, reserpine administration leads to closing of the eye and asubstantial fall in rectal temperature.

The administration of some compounds of the invention antagonizes theeffects of reserpine, which demonstrates the antidepressant activity ofthese de compounds.

EXAMPLE 41: ANTIHYPERTENSIVE ACTIVITY

The arterial blood pressure was determined on the rat's tail accordingto the method described by BYROM and WILSON (1938). This method consistsin measuring the pressure required to interrupt the blood flow in thecaudal artery. To this end, a pneumatic rubber cuff linked to a NARCOtype PE 300 electrosphygmomanometer is attached to the rat's tail 2centimeters from the base, so as to compress the caudal artery.

A pneumatic type pulsation sensor permits auscultation of the artery 1cm downstream from the cuff. The value of the systolic blood pressure isthat at which reappearance of the systolic/diastolic fluctuations isobserved during deflation of the cuff.

The products of the invention are administered orally in suspension inacacia syrup in a volume of 1 ml.kg⁻¹.

The pressure is measured before any treatment is given, and 2 hours and24 hours after the treatment.

Some products of the invention significantly lower the arterial bloodpressure.

EXAMPLE 41: PHARMACEUTICAL COMPOSITION TABLET

Tablets containing 20 mg of3-methyl-6-(3-morpholinopropyl)benzoxazolinone

    ______________________________________                                        Preparation formula for 1000 tablets.                                         ______________________________________                                        3-Methyl-6-(3-morpholinopropyl)-                                                                     20 g                                                   benzoxazolinone                                                               Wheat starch           15 g                                                   Corn starch            15 g                                                   Lactose                65 g                                                   Magnesium stearate      2 g                                                   Silica                  1 g                                                   Hydroxypropylcellulose  2 g                                                   ______________________________________                                    

What is claimed is:
 1. A compound selected from those formula (I):##STR24## in which: R₁ denotes a hydrogen atom or a lower alkyl groupoptionally substituted with a hydroxyl group,R₂ and R₃ form, with thenitrogen atom to which they are attached a morpholino group, X denotes ahydrogen atom, Y denotes a hydroxyl group, Z denotes a hydrogen atom,and T denotes a hydrogen atom or lower alkyl group,the term lowerindicating that the groups so described have 1 to 6 carbon atomsinclusive, their stereoisomers, their quaternary ammonium salts andtheir addition salts with a pharmaceutically, acceptable acid.
 2. Acompound as claimed in claim 1 which is3-methyl-6-(1-hydroxy-3-morpholinopropyl)benzoxazolinone, or an additionsalt thereof with a pharmaceutically, acceptable acid.
 3. Apharmaceutical composition suitable for alleviation of pain containing,as active analgestic principle, at least one compound as claimed inclaim 1, in combination with one or more pharmaceutically, acceptable,nontoxic, inert vehicles or excipients.
 4. A pharmaceutical compositionas claimed in claim 3, wherein the compound is3-methyl-6-(1-hydroxy-3-morpholinopropyl)benzoxazolinone or an additionsalt thereof with a pharmaceutically-acceptable acid,
 5. A method fortreating a living animal body afflicted with pain, comprising the stepof administering to the said living animal an effective analgesic amountof a compound selected from those of formula (I): ##STR25## in which: R₁denotes a hydrogen atom or a lower alkyl group optionally substitutedwith a hydroxyl group,R₂ and R₃ form, with the nitrogen atom to whichthey are attached a morpholino group, X denotes a hydrogen atom, Ydenotes a hydroxyl group, Z denotes a hydrogen atom, and T denotes ahydrogen atom or lower alkyl group, the term "lower" indicating that thegroups so described have 1 to 6 carbon atoms, inclusive, theirstereoisomers, their quaternary ammonium salts, and their addition saltswith a pharmaceutically-acceptable acid, which is suitable for thealleviation of said condition.
 6. A method as claimed in claim 5,wherein the compound is3-methyl-6-(1-hydroxy-3-morpholinopropyl)benzoxazolinone or an additionsalt thereof with a pharmaceutically-acceptable acid.